The pseudopterosins are compounds produced by the Caribbean sea whip Pseudopteragoria elisabethae. These compounds are exemplified by the structures shown below, pseudopterosin A (Compound 1) and E (Compound 2),1 which are remarkably active antiinflammatory agents2 that were discovered by W. Fenical and collaborators. 
The analgesic activity of Compound 1 (administered subcutaneously) is several fold greater than that of indomethacin,2 and that of Compound 2 is some 50 times greater.3 This potency and the fact that the biological mode of action of Compounds 1 and 2 appears to be novel2 have made these substances (and their analogues) attractive targets for synthetic and for biological/biochemical research.
Further interest in the pseudopterosins derives from their commercial use as topical antiinflammatory agents in the cosmetic field and the limited supply available from natural sources.4 A number of laboratories have described studies on the total synthesis of pseudopterosins. The earliest syntheses were developed by C. A. Broka and co-workers5 and in these laboratories,6 including the first sterocontrolled enantioselective syntheses of Compounds 1 and 2 from either (+)-menthol6a or (S)-citronellal.6b Subsequently, a variety of additional synthetic approaches have been developed b other groups.7-10 Although the more recent syntheses involve fascinating and elegant design, they appear to fall short of practicality.
One preferred embodiment of the present invention is a new synthetic route to pseudopterosin aglycone (3): 
an intermediate for the synthesis of a group of antiinflammatory natural products including pseudopterosin A (Compound 1) and E (Compound 2).
The synthetic pathway of the present invention is outlined below in Scheme I, and starts with the abundant and inexpensive (S)-(xe2x88x92)-limonene and its long-known cyclic hydroboration product (Compound 4) and leads to the chiral hydroxy ketone (Compound 6). Conversion of Compound 6 to Compound 10, followed by a novel aromatic annulation produced Compound 15 which underwent highly diasterioselective cyclization to afford the protected pseudopterosin aglycone (Compound 16). The naturally occurring pseudopterosins such as (Compound 1) and (Compound 2) are readily available from this intermediate. This intermediate will also serve as a source of novel synthetic pseudopterosin compounds. 
Thus, one preferred embodiment of the present invention is a new process for the synthesis of pseudopterosin compounds which has a number of advantages over previously known methods; including (1) an inexpensive chiral starting material (limonene), (2) the use of common or readily available reagents, (3) stereocontrol, (4) simplicity of execution, (5) good yields, and (6) directness. In addition, this synthesis illustrates a number of new and potentially widely useful synthetic methods of noteworthy aspects of stereocontrol and site selectivity.
The present invention is thus directed to the synthetic process outlined in Scheme 1, to the novel intermediates obtained therein, and to the uses of these compounds as synthetic precursors to the pseudopterosins. Other embodiments and aspects of the present invention include the novel synthetic procedures described herein, as detailed below.
As described above, the starting material for the present synthesis of pseudopterosin compounds was diol mixture (4) which can be obtained in nearly quantitative yield from (S)-(xe2x88x92)-limonene by cyclic hydroboration and alkaline peroxide oxidation.11 Although this mixture of diols (nearly 1:1) is readily available in quantity, it is believed that this mixture has neither been separated nor been used as starting material in a stereocontrolled synthesis. Neither distillation nor chromatographic methods allow separation of the mixture. Nonetheless, it has been found that the diastereomeric mixture can be utilized for synthesis using the novel separation process, as outlined above in Scheme 1.
Referring to Scheme 1, the process of the present invention was started by subjecting a nearly 1 to 1 diastereomeric mixture of diols (4) (54:46 C(8)) to selective oxidation at C(2) upon exposure to 1.5 equiv of sodium hypochlorite12 in aqueous acetic acid. This formed the diastereomeric mixture of hydroxy ketones 5 in excellent yield. Exposure of this hydroxy ketone mixture to isopropenyl acetate in isopropyl ether at 23xc2x0 C. using Amano PS lipase as the catalyst resulted in selective acetylation of the (8S)-hydroxy ketone after 17 h. Flash chromatography of the resulting mixture on silica gel afforded the desired (8R)-alcohol 6 (36% based on 5) as an oil (ratio 8R/8S=99:1 as determined by HPLC analysis of the corresponding p-nitrobenzoate ester) and the acetate of the (8S)-diastereomer of 6. Oxidation of 6 in a CH2Cl2xe2x80x94H2O system with sodium hypochlorite and 2,2,6,6-tetramethyl-1-piperidinyloxy radical (TEMPO) as catalyst13 at pH 8 gave keto aldehyde 7 in 92% yield. Wittig -Vedejs E-selective olefination14a of 7 using the ylide 814b as reagent in dimethozyethane produced the E-diene 9 in excellent yield, as shown in Scheme 1, without the loss of stereochemical integrity at the labile C(8) position.
With the successful establishment of three of the four stereocenters of pseudopterosin aglycone (3), the next task called for in the synthetic plan was the attachment of the aromatic ring, i.e., the conversion 9-14 in Scheme 1. This was accomplished using a new aromatic annulation protocol starting with Mukaiyama-type Michael coupling of the enol silyl ether 10 and the functionalized xcex1,xcex2-enone 11.15,16 This coupling product was obtained in 74% yield (correcting for a small amount of recovered 9) using 1.1 equiv of SnCl4 as the catalyst in CH2Cl2 at xe2x88x9278xc2x0 C. of 40 min. Treatment of Compound 12 with ethanolic KOH at 0xc2x0 C. effected aldol cyclizaton to a xcex2-hydroxy ketone which was dhydrated by treatment with SOCl2-pyridine at 23xc2x0 C. for 1 h to form the xcex1,xcex2-enone 13. The enol tert-butyldimethylsiyl (TBS) either of Compound 13 was prepared by deprotonation (alpha to methyl) and silylation with TBS-triflate, and then the resulting ether was aromatized by stirring with activated MnO2 (Aldrich Co., Milwaukee) in methylcyclohexane at 70xc2x0 C. for 36 h to provide the aromatic hydronaphthalene 14 in 90% overall yield from 13.
It was found that the MnO2-induced aromatization process proceeds more readily and in higher yield with methylcyclohexane as solvent than in benzene or toluene as solvent17 and that by using the dry MnO2-methylcyclohexane system aromatization of a wide range of Compound 1,4- and 1,3-cyclohexadienes can be effected efficiently. A summary of these studies is presented below. In contrast to the success achieved using the MnO2-methylcyclohexane aromatization system, a number of other oxidants that have previously been recommended for aromatization failed, including (q) Pd-X, (2)dichlorodicyano-quinone, (3) o-chloranil, (4) 2,6-dichloro-1,4-benzo-quinone, and (5) Cr(CO)3.3CH3CN, norbornene.18
Desilylation of Compound 14 (Bu4NF in THF) and reaction with CH3xe2x80x94SO2Clxe2x80x94Et3N in CH2Cl2 provided the mesylate 15 which upon treatment with 5 equiv of CH3SO3H in CH2Cl2 at xe2x88x9250xc2x0 C. underwent highly diasteroselective cationic cyclization (25:1) to form 16 in very high yield. Reaction of Compound 16 with MeMgBr produced cleanly the monophenol 17 which was debenzylated to give pseudopterosin aglycone (3). The various pseudopterosins may be accessed from 17 or 3 by procedures previously developed in these laboratories.6 Comparison of synthetic 3 [xcex1]23Dxe2x88x9295 (c=1, CHCl3) with authentic 36 revealed identical IR, 1H NMR, 13C NMR, and high-resolution mass spectra.
It is interesting that the methanesulfonic acid cyclization of TBS ether 14 afforded primarily (8:1) the product 18, corresponding to 16 with the (S)-configuration at C(1). This remarkable difference in the sterochemistry of cationic cyclization of Compound 14 and 15, clearly dependent on the electron-donating properties of TBSO vs. MsO, is most readily explained as due to a difference in mechanistic pathway, as shown in Scheme 2. 
The pathway from 15 to 16 probably involves direct 6-membered ring closure of allylic cation 19. However, as shown above in Scheme 2, the pathway from 14 to 18 can most reasonably be explained by cyclization of allylic cation 19 to the 5-membered spiro cation 2019 followed by 1,2-rearrangement with 5xe2x86x926 ring expansion. Thus, the differences in stereopreferences for formation of Compound 16 and 18 reflect stereoelectronic preferences of the intermediate steps 19xe2x86x9216 and 19xe2x86x9220.
It is believed that the synthetic process described herein and outlined in Scheme 1 provides a very direct and practical route for the synthesis of pseudopterosin compounds in quantity. In addition, a number of the steps illustrated in Scheme 1 are also of broader interest from the viewpoint of general synthetic methodology, including (1) the use of an inexpensive, recoverable lipase to effect separation of the diastereomers of 5, (2) the new procedure for the aromatic annulation of 9xe2x86x9214, (3) the remarkably stereoselective cyclizations of Compound 15xe2x86x9216 and 14xe2x86x9218, and (4) the superiority of MnO2 as a mild reagent for aromatization of cyclohexadienes. Accordingly, these steps are considered to be particularly preferred embodiments of the present invention.
With regard to the usefulness of dry MnO2 in methylcyclohexane as a reagent for the aromatization of cyclohexadienes, presented below are additional results that have been obtained with a diverse collection of substrates, as summarized in Table 1. The aromatization reactions, which were generally monitored by thin-layer chromatography, proceed at varying rates as shown in Table 1. The aromatization of dimethyl trans-1,2 dihydrophtyhalate was found to be considerably faster than that of various alkyl- or oxy-substituted dihydrobenzenes, an indication that the first step in the process may be a hydrogen atom rather than a hydride abstraction.